Functional analysis of two novel TBX5 variants present in individuals with Holt-Oram syndrome with different clinical manifestations.

Holt-Oram syndrome (HOS) is a rare disorder characterized by cardiac and upper-limb defects. Pathogenic variants in TBX5-a gene encoding a transcription factor important for heart and skeletal development-are the only known cause of HOS. Here, we present the identification and functional analysis of two novel TBX5 pathogenic variants found in two individuals with HOS presenting distinct phenotypes. The individual with the c.905delA variant has a severe cardiac phenotype but mild skeletal defects, unlike the individual with the c.246_249delGATG variant who has no cardiac problems but severe upper limbs malformations, including phocomelia. Both frameshift variants, c.246_249delGATG and c.905delA, generate mRNAs harbouring premature stop codons which, if not degraded by nonsense mediated decay, will lead to the production of shorter TBX5 proteins, p.Gln302Argfs*92 and p.Met83Phefs*6, respectively. Immunocytochemistry results suggest that both mutated proteins are produced and furthermore, like the wild-type protein, p.Gln302Argfs*92 mutant appears to be mainly localized in the nucleus, in contrast with p.Met83Phefs*6 mutant that displays a higher level of cytoplasmic localization. In addition, luciferase activity analysis revealed that none of the TBX5 mutants are capable of transactivating the NPPA promoter. In conclusion, our results provide evidence that both pathogenic variants cause a severe TBX5 loss-of-function, dramatically reducing its biological activity. The absence of cardiac problems in the individual with the p.Met83Phefs*6 variant supports the existence of other mechanisms/genes underlying the pathogenesis of HOS and/or the existence of an age-related delay in the development of a more serious cardiac phenotype. Further studies are required to understand the differential effects observed in the phenotypes of both individuals.

[Fulminant myocarditis]. / Miocardite fulminante - a propósito de um caso clínico.

A 46-year-old woman was admitted due to diplopia because of ophthalmoplegia, which improved with corticosteroid therapy. Eight days later, she was admitted with fulminant myocarditis in cardiogenic shock, with severe left ventricular dysfunction and frequent episodes of nonsustained ventricular tachycardia. As there was no clinical improvement, an endomyocardial biopsy was performed that revealed inflammatory infiltrate, vasculitis, and PCR positive for cytomegalovirus, Epstein-Barr virus, parvovirus B19 and enterovirus. Left ventricular function recovered with heart failure treatment and corticosteroids. Three months later, after progressive withdrawal of prednisolone, there was recurrence of myocarditis and left ventricular dysfunction, which was successfully treated by restarting corticosteroid therapy. One month later she was readmitted with fulminant myocarditis which again responded to steroids. She intermittently presented cutaneous purpura lesions. At this time the provisional diagnosis was vasculitis and she started monthly cycles of cyclophosphamide. Before the second cycle she was admitted with pneumonia and ventricular dysfunction and died.

Implementation of a pre-hospital network favoring primary angioplasty in STEMI to reduce mortality: the Algarve Project.

OBJECTIVE: To analyze the impact of reperfusion by either primary percutaneous coronary intervention (PPCI) or fibrinolysis, and mortality rates of a pre-hospital fast-track network for treating patients with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A pre-hospital network for STEMI patients, designated the Green Lane for Acute Myocardial Infarction (GL-AMI), has been implemented in the southern region of Portugal --the Algarve Project. We performed an observational study based on a prospective registry of 1338 patients admitted to Faro Hospital between 2004 and 2009, classified in two groups according to the method of admission: emergency department group (EDG) and GL-AMI group (GLG). More patients from GLG were reperfused (p < 0.0001). PPCI was the preferred method of reperfusion, 73.1% in GLG and 45.3% in EDG. Time delays were significantly shorter in GLG, except for pre-hospital delay: pre-hospital delay (p = 0.11); door-to-needle (p < 0.0001); door-to-balloon (p < 0.0001); and delay between symptoms and reperfusion (p < 0.0001). In-hospital mortality (4.3% vs 9.2%, p = 0.0007) and 6-month mortality (6.3% vs 13.8%, p < 0.0001) were significantly lower in GLG. CONCLUSIONS: The Algarve Project significantly reduced the time delay between onset of symptoms and reperfusion, significantly increased the rate of reperfusion, and significantly reduced in-hospital and six-month mortality.

Giant Left Ventricular (Pseudo?) Aneurysm Complicating Anterior Myocardial Infarction.

The differential diagnosis of true aneurysms and pseudoaneurysms is challenging, and multimodality cardiac imaging is often necessary. We report a case in which the limitations of these techniques are exposed, showing that post-operative evaluation of tissue layers remains the gold standard in establishing this diagnosis. (Level of Difficulty: Beginner.).

Female gender: an independent factor in ST-elevation myocardial infarction.

INTRODUCTION: Cardiovascular disease is the leading cause of death in women. In ST-elevation myocardial infarction (STEMI) in particular, the question has been raised whether specific characteristics of women confer a worse prognosis. OBJECTIVE: To evaluate the differences in STEMI patients between the genders in cardiovascular risk profile, clinical presentation, therapeutic approach and in-hospital and 6-month mortality rates. METHODS: We analyzed 1578 patients admitted consecutively with STEMI during a 7-year period (from January 13, 2002 to December 31, 2008). The patients were divided into two groups according to gender, and compared in terms of baseline clinical and demographic characteristics, pre-hospital and in-hospital delay, clinical presentation on admission, reperfusion therapy, severity of coronary disease and in-hospital and 6-month mortality. RESULTS: Of the 1578 patients, 26% were female. Women were older (by 8 years), and had a higher cardiovascular risk profile. On admission, their clinical presentation was more severe, with a higher frequency of anterior myocardial infarction and acute heart failure symptoms. Women had longer ischemic times and lower rates of reperfusion therapy. Mortality in women was significantly higher than in men, both in-hospital (17.5 vs. 5.3%) and at 6 months (23.5% vs. 8.2%). After adjustment in multivariate analysis, mortality in women remained higher. CONCLUSIONS: The adverse demographic and clinical profile could partially explain the worse prognosis of STEMI in women. This, together with longer pre-hospital delays, led to underuse of reperfusion therapy. Even so, female gender by itself had a negative and independent influence on mortality in STEMI patients.

A case of rare longevity of tetralogy Fallot.

Tetralogy of Fallot is one of the most common forms of cyanotic congenital heart disease. In the absence of surgical correction it has high early mortality, with most patients dying in childhood. Survival beyond the seventh decade of life is extremely rare. The authors present the case of a patient with uncorrected tetralogy of Fallot who survived to the age of eighty. The longevity of this patient is certainly linked to the association between a large ventricular septal defect and "balanced" pulmonary stenosis: sufficiently mild not to cause severe hypoxia, but significant enough to protect the pulmonary vasculature.

Apical ballooning syndrome--a review of five cases.

INTRODUCTION: Takotsubo syndrome (apical ballooning syndrome) was described for the first time in Japan, at the beginning of the 1990s. It is characterized by the acute onset of extensive but transient akinesia of the apical and mid portions of the left ventricle, in the absence of significant coronary disease. OBJECTIVE: We describe five patients who were admitted to our hospital with this new syndrome between June 2004 and December 2005. These patients represented 0.8% of a total of 613 patients admitted for acute myocardial infarction in that period. RESULTS: All the patients were female, with a mean age of 60.2+/-10.3 years. Chest pain was the most frequent clinical presentation (n=5). A possible triggering factor, intense emotional stress, was identified in two patients. At admission, the electrocardiogram showed ST elevation in two patients and Q waves in the precordial leads in one. All cases had negative T waves in the precordial leads at some point. All patients had increased troponin levels but only two had elevated cardiac enzymes. The echocardiogram revealed extensive akinesia of the apical and mid portions of the left ventricle, and a thrombus was observed in one patient. Coronary angiography showed no significant lesions. Currently, all five patients are virtually asymptomatic, with regression of left ventricular wall-motion abnormalities on echocardiography. CONCLUSION: This is the first series of apical ballooning syndrome described in Portugal. Although rare, it should be considered in the differential diagnosis of acute myocardial infarction. Despite its transient nature, in the acute phase it can be a serious condition. More research is needed to better characterize this new entity.

Are degenerative changes in the aortic valve an additional important marker of atherosclerosis?

BACKGROUND AND AIM: Degenerative changes of the mitral annulus are associated with atherosclerotic disease. It has recently been suggested that degenerative changes in the aortic valve may also be associated with atherosclerosis. The intima-media thickness of the carotid arteries has been used as one of the best and earliest markers of atherosclerosis. The aim of this study was to evaluate whether the additional presence of degenerative changes in the aortic valve in coronary patients with mitral annular degenerative disease reflects different degrees of intima-media thickness as assessed by carotid ultrasonography. METHODS: The study group included 55 patients admitted for myocardial infarction who presented with degenerative changes of the mitral annulus assessed by echocardiography. Exclusion criteria were moderate or severe valvular heart disease and chronic renal failure. All patients underwent echocardiography, cardiac Doppler and carotid ultrasonography. Based on the echocardiographic findings, two sub-groups were formed: 1--with degenerative changes of the aortic valve; and 2--without degenerative changes of the aortic valve. Carotid ultrasonography was performed with a 7.5-10 MHz linear transducer and the following parameters were evaluated: 1--bilateral measurement of intima-media thickness in the common carotid artery; 2-- incidence of atheromatous plaques in the carotid arteries, and 3--incidence of >50% lesion in the internal carotid arteries assessed by pulsed Doppler (Vmax >125 cm/s). RESULTS: Thirty-three patients (aged 71.6 +/- 7.1 years), 21 men and 12 women, did not present degenerative changes in the aortic valve. The other group consisted of 22 individuals (aged 72.9 +/- 6.8 years), 14 men and 8 women, who did have such changes. Differences in age and gender distribution between the two groups were not significant. Patients with degenerative aortic valve disease had greater intima-media thickness than the control group (1.6 +/- 0.3 mm versus 1.3 +/- 0.4 mm, p < 0.001). Fifteen (68%) patients with aortic degenerative disease had plaques in the carotid arteries compared to 11 (33%) patients in the control group (p < 0.05). No significant differences were found between the two groups regarding the incidence of >50% atherosclerotic lesion in the internal carotid artery (22% versus 12%; NS). CONCLUSIONS: Patients with degenerative changes in the aortic valve presented significantly greater intima-media thickness and a higher incidence of atherosclerotic plaques than the control group, suggesting that their presence may constitute an additional important marker of severity of atherosclerotic disease.

The value of electrocardiography for differential diagnosis in wide QRS complex tachycardia.

Correct diagnosis in wide QRS complex tachycardia remains a challenge. Differential diagnosis between ventricular and supraventricular tachycardia has important therapeutic and prognostic implications, and although data from clinical history and physical examination may suggest a particular origin, it is the 12-lead surface electrocardiogram that usually enables this differentiation. Since 1978, various electrocardiographic criteria have been proposed for the differential diagnosis of wide complex tachycardias, particularly the presence of atrioventricular dissociation, and the axis, duration and morphology of QRS complexes. Despite the wide variety of criteria, diagnosis is still often difficult, and errors can have serious consequences. To reduce such errors, several differential diagnosis algorithms have been proposed since 1991. However, in a small percentage of wide QRS tachycardias the diagnosis remains uncertain and in these the wisest decision is to treat them as ventricular tachycardias. The authors' objective was to review the main electrocardiographic criteria and differential diagnosis algorithms of wide QRS tachycardia.

Holt-Oram syndrome: a case report.

Holt-Oram syndrome is clinically characterized by morphological abnormalities of the upper limbs and congenital cardiac defects. Although the disease is congenital, the diagnosis may only be made later in life. It is a rare autosomal dominant disorder, caused by a mutation in the TBX5 gene located on chromosome 12, but sporadic cases have also been reported. We describe the case of a 75-year-old man with known morphological alterations of the upper limbs since birth and congenital cardiac defect (atrial septal defect), who later in life also manifested with advanced atrioventricular block.

[Syncope unit: experience of a center using diagnostic flowcharts for syncope of uncertain etiology after initial assessment]. / Unidade de Síncope - Experiência de um centro com base em organigramas de decisão para síncope de etiologia incerta após a avaliação inicial.

INTRODUCTION AND OBJECTIVES: Syncope is a common symptom that leads to 1% of admissions to hospital emergency departments, and is associated with high costs to the health system. The cardiology department of Faro Hospital has had a syncope unit since July 2007. The aim of this study is to analyze its results in terms of etiological diagnosis and treatment of syncope, using diagnostic flowcharts based on European Society of Cardiology (ESC) guidelines. METHODS: We conducted a retrospective study of all patients referred to the syncope unit of Faro Hospital between July 2007 and August 2011. We analyzed demographic data, characteristics of syncopal episodes, diagnostic methods, etiology of syncope and treatment. The percentages of syncope of cardiac and uncertain etiology were compared with data from other international syncope units. Statistical analysis was performed using SPSS version 13.0. RESULTS: Of the 304 patients referred to the syncope unit for loss of consciousness, 245 (80.7%) had syncope. Most had reflex syncope (52.2%), 20% had cardiac syncope, 15.6% had orthostatic hypotension, and in 12% of cases etiology remained undetermined. The percentages of cardiac and uncertain etiology were similar to data published by other syncope units. CONCLUSIONS: The Faro Hospital syncope unit obtained similar results to those published by other international syncope units through application of diagnostic flowcharts for etiological diagnosis of syncope. The flowcharts presented can be of value for the proper application of ESC guidelines on syncope.

A 72-year-old woman with an uncorrected tetralogy of Fallot presenting with possible pulmonary endocarditis: a case report.

INTRODUCTION: Tetralogy of Fallot is one of the most common forms of cyanotic congenital heart disease and in the absence of surgical correction it has an elevated early mortality, with most patients dying in childhood.The authors reported this case because of the unusual course of an uncorrected tetralogy of Fallot. There are only a few reports of patients with an uncorrected tetralogy of Fallot who reach an advanced age and to the best of our knowledge this is the first case report of a possible endocarditis in a patient with an uncorrected tetralogy of Fallot who is older than 70 years. CASE PRESENTATION: The authors present a case of a 72-year-old Caucasian woman with uncorrected tetralogy of Fallot who was admitted with fever and heart failure to our Cardiology Department with possible infective endocarditis. CONCLUSIONS: The longevity of this patient is probably due to the association between a large ventricular septal defect, a balanced subpulmonary stenosis and to the presence of systemic hypertension. After empiric antibiotic therapy, the patient was discharged and no surgical intervention was performed due to her previous benign evolution.

Pseudoaneurysm inside of a true aneurysm.

Left ventricular pseudoaneurysms and true aneurysms are two possible complications of myocardial infarction. However, while pseudoaneuryms require urgent surgical resection, true aneuryms can often be managed medically, making imperative an accurate diagnosis.The authors describe a case of a delayed rupture of a true aneurysm that was contained and gave rise to a pseudoaneurysm inside of a true aneurysm. The echocardiography allowed the differential diagnosis for a timely surgical intervention which resulted in the patient's full recovery.